Loneliness and analgesic overuse among low-dose estrogen-progestin users in Japan

This self-administered web-based questionnaire survey was conducted on May 26 and 27, 2023. The questionnaire used in this study was developed for this study [Supplementary]. Women in their 20 s and 30 s were randomly selected from a research company’s web panel balancing the residential area (Macromill, Inc.). Questionnaires were emailed to a randomly selected group of women registered for the web panel. In this survey, the target sample size was set at 256 respondents in their 20 s and 256 in their 30 s, with the aim of understanding the actual conditions of LEP users. This sample size was determined as a practical and realistic number that would allow for the identification of trends within a defined population and enable comparisons between key subgroups (based on cutoff values for loneliness scale). Furthermore, due to the lack of sufficient preliminary data, it was difficult to design a precise sample size based on detailed estimations or statistical testing. Therefore, for this initial exploratory survey, the sample size of 256 individuals in their 20 s and 256 in their 30 s was deemed appropriate. The survey was closed when the number of valid responses reached 258 in age 20 s and 258 in age 30s. LEP users were screened based on a question in Table  1 . For LEP, the Japan Pharmaceutical Reference indicates “precaution for patients with certain backgrounds” and that LEP may make “patients over 40 years of age” more susceptible to and may contribute to cardiovascular disorders such as myocardial infarction [ 36 ]. Thus, the age of participants in this study was limited to 39 years or younger. Pregnant and lactating women were excluded because of the contraindications in Japan Pharmaceutical Reference [ 36 ]. Individuals who had registered as healthcare professionals in the web panel of a research company (Macromill, Inc.) were excluded, as their professional knowledge about menstruation could significantly influence their use of analgesics compared to the general population. The LEP classification question lists multiple options. Respondents could choose more than one option, but if more than one is selected, it is not counted as a valid response. Table 1 Question about LEP use Question. What low-dose pill(s) are you currently using? (multiple responses allowed) Oral contraceptive  ◌Ange ◌Tricular ◌Synphase ◌ Marvelon ◌ Labellefeuille ◌ Favoire Low-dose estrogen-progestin  ◌ Gemina ◌ YAZ ◌ Yaz-Flex ◌ Friewell LD ◌ Frewell ULD ◌ Lunavel ◌ DROETI  ◌Others  ◌ I have never used low-dose pills Question about LEP use The Three-Item Loneliness Scale (TIL) has been widely used to measure loneliness in a simplified format [ 37 , 38 ]. TIL was established based on the 20-item Revised UCLA Loneliness Scale (R-UCLA) to mitigate the response burden and was validated by the associations with several indicators, such as R-UCLA scores, depressive symptoms, marital status, and living arrangements. The TIL scale represents feelings of lack of companionship, feeling left out and feeling isolated from others [ 10 ]. The Japanese translated TIL Scale showed essential unidimensionality and characteristics to differentiate among respondents at different levels of loneliness [ 38 ]. The TIL score ranges from 3 to 9, with a higher score indicating greater loneliness [ 10 ]. The TIL cut-off value is 6 [ 38 ]. This survey included the 14-Item Health Literacy Scale (HLS-14). HLS-14 is a useful tool for assessing cognitive and social skills underlying the motivation and ability of individuals to gain access to, understand, and use information in ways that promote and maintain good health [ 39 ]. The HLS-14 ranges from 14 to 70, with a higher score indicating better health literacy [ 39 ]. Also, this survey included the Pittsburgh Sleep Quality Index (PSQI). PSQI was developed to measure general sleep quality and is one of the recommended questionnaires for the study of global sleep and insomnia symptoms [ 40 – 42 ]. The PSQL score ranges from 0 to 21, with a higher score indicating worse sleep quality [ 41 ]. The PSQL cut-off value is 6 [ 41 ]. The main items investigated were age, TIL score, HLS-14 score, PSQI score, PMS mental symptoms, PMS physical symptoms, menstrual pain, endometriosis, frequency of headache per month, LEP patient card use, menstrual app use, LEP dose recording, self-recording of menstrual symptoms, kampo medicine use, consultation about LEP with pharmacists, concomitant analgesic use (≥ 1 day per month), frequency of concomitant analgesic use per month, concomitant analgesic use for menstrual pain, headache, low back pain, or prophylaxis, and concomitant analgesic dose recording. LEP patient card includes information about taking LEP and symptoms of thromboembolism for the benefit of the doctor who sees the patient. It is recommended that those taking LEP carry LEP patient card. These questionnaire items are listed in the survey form; please refer to it [Supplementary]. Pearson’s chi-squared test was used to assess differences between age 20 s and 30 s, concomitant analgesic use ≥ 10 days per month and less frequent concomitant analgesic use. To examine multicollinearity in the logistic regression analysis, a diagnosis was made using the Variance Inflation Factor (VIF); a commonly used threshold for VIF of 10 was used as a criterion and any variable with a VIF above 10 was judged to be of concern for multicollinearity [ 43 ]. The explanatory variables were selected on the basis that the number of events per explanatory variable should be at least 10 [ 44 ]. Based on these criterions, appropriate selection of explanatory variables was made. First logistic regression analysis was performed with TIL ≥ 6 ( N  = 236) (vs. TIL ≤ 5 ( N  = 280)) as the outcome variable based on the cut-off value of 6. Only variables considered to have strong clinical or theoretical relevance to the outcome were selected as candidate explanatory variables. Loneliness (TIL ≥ 6) was hypothesized to be associated with the concurrent use of analgesics (≥ 1 day per month) or analgesic overuse (≥ 10 days per month). Univariate regression analysis revealed a significant association between loneliness and the concurrent use of analgesics (≥ 1 day per month), whereas no significant association was found with analgesic overuse (≥ 10 days per month). Based on this preliminary analysis, analgesic overuse (≥ 10 days per month) was not included in the logistic regression model; instead, concurrent use of analgesics (≥ 1 day per month) was selected. Factors thought to be associated with the intensity of loneliness included high headache frequency, endometriosis, physical symptoms of PMS, health literacy, sleep quality, and age. Therefore the explanatory variables included in the logistic regression model were: concomitant analgesic use (≥ 1 day per month), headache frequency (≥ 10 days per month), endometriosis, physical symptoms of PMS, HLS-14 ≥ 53, PSQI ≥ 6, and age 30–39 years. A high frequency of headaches was considered a contributing factor to feelings of loneliness. It was also associated with increased use of concomitant analgesics. According to the third edition of the International Classification of Headache Disorders [ 30 ], analgesic use on 10 or more days per month meets the diagnostic criteria for medication overuse headache (MOH). Accordingly, the threshold for frequent analgesic use was set at 10 days per month, based on this criterion. The cut-off for HLS-14 (≥ 53) was based on the median score of 52. PSQI ≥ 6 was chosen because a score of 6 or higher indicates poor sleep quality [ 40 ]. The maximum variance inflation factor (VIF) was 1.10, indicating no multicollinearity concerns. The whole model test, which compares the fitted logistic regression model against a model with intercept-only parameters, was significant ( p  < 0.001). The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.678. A second logistic regression analysis was performed using concomitant analgesic use ≥ 10 days per month ( N  = 37) versus other cases ( N  = 479) as the outcome variable, due to its inclusion in the diagnostic criteria for MOH [ 30 ]. Explanatory variables in this model included headache frequency ≥ 10 days per month, endometriosis, concomitant analgesic use for low back pain, and concomitant analgesic use for menstrual pain. Variables such as HLS-14 ≥ 53, PSQI ≥ 6, and age 30–39 years were excluded, following the recommendation that at least 10 events per explanatory variable are required [ 44 ]. The maximum VIF was 1.08, confirming no multicollinearity. The whole model test was again significant ( p  < 0.001), and the AUC of the ROC curve was 0.923. Statistical analysis was performed using JMP Pro ver. 17.0.0 (JMP Statistical Discovery LLC, Cary, NC). A p-value < 0.05 was considered statistically significant.

A flow chart of participants in this study is shown in Fig.  1 . A total of 516 valid responses were included in the analysis (258 in their 20 s, 258 in their 30 s). Only LEP users are included and OC users are excluded. LEP users for contraceptive purposes are included. Missing data is not included in valid responses. Fig. 1 Flowchart for selection of the questionnaire respondents The study population was selected by prescreening of women who were LEP users. The participants were registered members at Macromill, Inc. Among those who were pre-screened, 5.9% in of women in their 20 s and 3.7% of those in their 30 s were enrolled in the main study. Only LEP users are included and OC users are excluded. LEP users for contraceptive purposes are included. Missing data is not included in valid responses. There were no invalid responses because we excluded respondents who gave inappropriate answers Flowchart for selection of the questionnaire respondents The study population was selected by prescreening of women who were LEP users. The participants were registered members at Macromill, Inc. Among those who were pre-screened, 5.9% in of women in their 20 s and 3.7% of those in their 30 s were enrolled in the main study. Only LEP users are included and OC users are excluded. LEP users for contraceptive purposes are included. Missing data is not included in valid responses. There were no invalid responses because we excluded respondents who gave inappropriate answers Table  2 shows the backgrounds of the LEP users. The median score was 52 for HLS-14 and 5 for TIL. The percentage with PSQI ≥ 6, which indicates low quality of sleep [ 42 ], was 56.6% ( N  = 292). Concomitant analgesic use (≥ 1 day per month) was reported by 64.1% ( N  = 331) of LEP users ( N  = 516). Of the LEP users, 20.0% ( N  = 103) reported concomitant use for contraceptive purposes. Significant differences between age groups in their 20 s and 30 s were found for menstrual pain ( p  < 0.001) and endometriosis ( p  = 0.002). Menstrual pain was more common among women in their 20 s, while endometriosis was more common among women in their 30s. Table 2 Backgrounds of participants N (%) Age 20s (%) Age 30s (%) Total 516 (100.0) 258 (100.0) 258 (100.0) HLS-14 ≥ 53 270 (52.3) 137 (53.1) 133 (51.6) TIL ≥ 6 236 (45.7) 120 (46.5) 116 (45.0) PSQI ≥ 6 292 (56.6) 152 (58.9) 140 (54.3) PMS mental symptoms 336 (65.1) 173 (67.1) 163 (63.2) PMS physical symptoms 371 (71.9) 188 (72.9) 183 (70.9) Menstrual pain 378 (73.3) 209 (81.0) 169 (65.5) Endometriosis 124 (24.0) 47 (18.2) 77 (29.8) Concomitant use for contraceptive purpose 103 (20.0) 50 (19.4) 53 (20.5) Headache 1–4 days per month 260 (50.4) 133 (51.6) 127 (49.2) Headache 5–9 days per month 63 (12.2) 30 (11.6) 33 (12.8) Headache 10 days or more per month 53 (10.3) 22 (8.5) 31 (12.0) LEP patient card using 160 (31.0) 84 (32.6) 76 (29.5) Menstrual app using 149 (28.9) 81 (31.4) 68 (26.4) LEP dose recording 167 (32.4) 92 (35.7) 75 (29.1) Menstrual symptoms self-recording 94 (18.2) 50 (19.4) 44 (17.1) Kampo using 29 (5.6) 17 (6.6) 12 (4.7) Concomitant analgesic using 331 (64.1) 165 (64.0) 166 (64.3) Concomitant analgesic using 10 days or more per month 37 (7.2) 13 (5.0) 24 (9.3) LEP Consultation with pharmacists 43 (8.3) 25 (9.7) 18 (7.0) HLS-14 14-Item Health Literacy Scale (range 14–70), TIL Three-Item Loneliness scale (range 3–9), PSQI  Pittsburgh Sleep Quality Index (range 0–21); PMS Premenstrual syndrome, LEP Low-dose estrogen-progestin Backgrounds of participants HLS-14 14-Item Health Literacy Scale (range 14–70), TIL Three-Item Loneliness scale (range 3–9), PSQI  Pittsburgh Sleep Quality Index (range 0–21); PMS Premenstrual syndrome, LEP Low-dose estrogen-progestin Table  3 shows characteristics among concomitant analgesic users (≥ 1 day per month). Concomitant analgesic use ≥ 10 days per month was reported by 11.2% ( N  = 37) of concomitant analgesic users (≥ 1 day per month) ( N  = 331). Among concomitant analgesic users (≥ 1 day per month) ( N  = 331), prophylactic use was reported by 12.7% ( N  = 42). Table 3 Characteristics of concomitant analgesic users (≥ 1 day per month) N (%) Age 20s (%) Age 30s (%) Concomitant analgesic using (≥ 1 day per month) in LEP users 331 (100.0) 165 (100.0) 166 (100.0) Concomitant analgesic used for menstrual pain 216 (65.3) 121 (73.3) 95 (57.2) Concomitant analgesic used for headache 262 (79.2) 126 (76.4) 136 (81.9) Concomitant analgesic used for low back pain 49 (14.8) 22 (13.3) 27 (16.3) Concomitant analgesic prophilaxic use 42 (12.7) 19 (11.5) 10 (6.0) Concomitant analgesic using 10 days or more per month 37 (11.2) 16 (9.7) 14 (8.4) Concomitant analgesic dose recording 35 (10.6) 23 (13.9) 12 (7.2) LEP Low-dose estrogen-progestin Characteristics of concomitant analgesic users (≥ 1 day per month) LEP Low-dose estrogen-progestin High TIL score was significantly associated with concomitant analgesic use (≥ 1 day per month) (odds ratio [OR] 1.76, 95% confidence interval [CI] 1.18–2.63, p  = 0.006), HLS-14 ≥ 53 (OR 0.54, 95% CI 0.37–0.78, p  = 0.001, which means low health literacy was significantly associated with high loneliness), and PSQI ≥ 6 (OR 2.71, 95% CI 1.86–3.94, p  < 0.001, which means low quality of sleep was significantly associated with high loneliness) (Fig.  2 ). Fig. 2 Factors associated with high TIL score Adjusted ORs and 95% CIs for TIL score ≥ 6 are shown for various attributes. Reference categories for calculating ORs were headache < 10 days per month, HLS-14 ≤ 52, PSQI ≤ 5, and age in 20s. * p  < 0.05, ** p  < 0.01, *** p  < 0.001. CI, confidence interval; OR, odds ratio; HLS-14, 14-item Health Literacy Scale (range 14–70); TIL, Three-Item Loneliness scale (range 3–9); PSQI, Pittsburgh Sleep Quality Index (range 0–21); PMS, premenstrual syndrome Factors associated with high TIL score Adjusted ORs and 95% CIs for TIL score ≥ 6 are shown for various attributes. Reference categories for calculating ORs were headache < 10 days per month, HLS-14 ≤ 52, PSQI ≤ 5, and age in 20s. * p  < 0.05, ** p  < 0.01, *** p  < 0.001. CI, confidence interval; OR, odds ratio; HLS-14, 14-item Health Literacy Scale (range 14–70); TIL, Three-Item Loneliness scale (range 3–9); PSQI, Pittsburgh Sleep Quality Index (range 0–21); PMS, premenstrual syndrome Concomitant analgesic use ≥ 10 days per month was significantly associated with headache ≥ 10 days per month (OR 36.58, 95% CI 14.92–89.70, p  < 0.001), endometriosis (OR 5.25, 95% CI 2.15–12.81, p  < 0.001), and concomitant analgesic use for low back pain (OR 4.67, 95% CI 1.65–13.18, p  = 0.004) (Fig.  3 .). Fig. 3 Factors associated with analgesic use ≥ 10 days per month. Adjusted ORs and 95% CIs for analgesic use ≥ 10 days are shown for various attributes. Reference categories for calculating ORs were headache < 10 days per month. * p  < 0.05, ** p  < 0.01, *** p  < 0.001. CI, confidence interval; OR, odds ratio Factors associated with analgesic use ≥ 10 days per month. Adjusted ORs and 95% CIs for analgesic use ≥ 10 days are shown for various attributes. Reference categories for calculating ORs were headache < 10 days per month. * p  < 0.05, ** p  < 0.01, *** p  < 0.001. CI, confidence interval; OR, odds ratio Table  4 shows backgrounds in concomitant analgesic use ≥ 10 days per month, which was significantly associated with self-recording of menstrual symptoms ( p  < 0.001) and LEP counseling with pharmacists ( p  < 0.001). Due to the small number of participants using concomitant analgesics ≥ 10 days per month, self-recording of menstrual symptoms and LEP counseling with pharmacists were excluded from the logistic regression model to limit the number of explanatory variables and avoid multicollinearity. Table 4 Characteristics of LEP users with concomitant analgesic use ≥ 10 days per month (a) (%) (b) (%) p -value N 37 (100.0) 479 (100.0) Self-recording of menstrual symptoms 15 (40.5) 79 (16.5) < 0.001*** LEP counseling with pharmacists 11 (29.7) 32 (6.7) < 0.001*** (a) Concomitant analgesic use ≥ 10 days per month (b) others, The Pearson’s chi-square test was conducted *** p  < 0.001. LEP, low-dose estrogen-progestin Characteristics of LEP users with concomitant analgesic use ≥ 10 days per month (a) Concomitant analgesic use ≥ 10 days per month (b) others, The Pearson’s chi-square test was conducted *** p  < 0.001. LEP, low-dose estrogen-progestin

This study aimed to investigate the prevalence of concomitant analgesic use and overuse among young LEP users in Japan. Of LEP users, 64.1% had concomitant analgesic use and 11.2% had concomitant analgesic use ≥ 10 days per month. We also clarified the factors associated with loneliness and concomitant analgesic overuse in LEP users. A high TIL score, indicating greater loneliness, was significantly associated with concomitant analgesic use (Fig.  2 ). Notably, loneliness was prevalent among the study population, with 45.7% of participants reporting a TIL score of 6 or higher (Table  2 ), which represents one of the key findings of this study. Given the high prevalence of loneliness among this group of LEP users, caution is warranted in interpreting the association between loneliness and concomitant analgesic use. Importantly, loneliness was not associated with concomitant analgesic overuse (see Methods section); instead, it was related to the concomitant use of analgesics, which may itself reflect a tendency toward higher overall medication use. This distinction suggests that while loneliness may not directly drive excessive use, it could be indicative of underlying patterns of frequent or habitual analgesic consumption. Concomitant analgesic use ≥ 10 days per month was significantly associated with endometriosis and concomitant analgesic use for low back pain (Fig.  3 ). Concomitant analgesic use ≥ 10 days per month was significantly associated with self-recording of menstrual symptoms (Table  4 ). These results suggest the importance of medication follow-up that takes into account loneliness and self-recording of menstrual symptoms. Attention by healthcare professionals to the context of concomitant analgesic overuse and loneliness may facilitate dialogue with patients and improve their quality of life. For clinical application and public health interventions, it is expected that concomitant analgesic overuse and loneliness will be recognized as modifiable factors. This study is the first to show that high loneliness was significantly associated with low health literacy, low quality of sleep, and concomitant analgesic use (Fig.  2 ). This result suggests that enhancement of health literacy may make it easier to reduce loneliness and that medical follow-up taking into account loneliness, sleep quality, and health literacy may be important. Women’s health literacy may contribute to decreased presenteeism (work productivity) and better health behaviors regarding the use of medicine or medical services [ 26 ]. It has been suggested that a trusting relationship with doctors is associated with health literacy and medication adherence [ 45 ]. The increased loneliness experienced during the pandemic may contribute to low digital health literacy, alienating these individuals from the benefits of digital technologies [ 46 ]. It is expected that building on a trusting relationship with a doctor and increasing digital health literacy will alleviate loneliness and improve medication adherence. Our findings suggest an association between loneliness and concomitant analgesic use, highlighting potential links with pain perception, mental health, and reproductive decision-making. A previous study demonstrated that increased loneliness and the severity of perceived social isolation are associated with the prevalence and incidence of pain [ 47 ], which is consistent with our observation that loneliness was linked to concomitant analgesic use. In this regard, examining the specific association between loneliness and concomitant analgesic overuse would have added further depth to our findings and warrants future investigation. Furthermore, previous studies have shown that loneliness is associated with depressive symptoms and heightened psychological distress, including among individuals postponing pregnancy [ 48 – 50 ]. These findings underscore the need for comprehensive medication follow-up that takes psychosocial factors into account. Biological pathways may underlie the observed associations. Social isolation has been shown to impair oxytocin release and alter pain perception, whereas social support may buffer pain sensitivity [ 51 , 52 ]. In particular, Transient Receptor Potential Melastatin (TRPM) channels—especially TRPM2 and TRPM3—are involved in pain signaling and oxidative stress responses, with evidence suggesting sex-specific differences in their function [ 53 , 54 ]. Oxidative stress–induced activation of TRPM2, which may be exacerbated by social isolation, could influence both pain and inflammatory pathways. The interplay between loneliness, oxytocin signaling, and TRP channel activity provides a biologically plausible mechanism linking psychosocial stress to altered pain regulation [ 55 ]. These mechanisms should be incorporated into future models investigating the relationship between loneliness and concomitant analgesic use, particularly among women. Concomitant analgesic overuse is significantly associated with frequent headaches, endometriosis, and use for low back pain (Fig.  3 ). Overuse for back pain may be linked to frailty, which is itself associated with low back pain. The Japan Frailty Scale (JFS), rooted in Kampo medicine, includes items on nocturia (0–2), low back pain (0–2), cold sensitivity (0–2), exhaustion (0–4), and age (0–1) [ 56 ]. Severe menstrual symptoms may contribute to concomitant analgesic overuse, and patients often self-record both symptoms and concomitant analgesic use (Table  4 ). This self-recording may increase symptom awareness. Detailed counseling based on such records is essential during medication follow-up. Prophylactic use of analgesics has not been thoroughly discussed. In this study, 12.7% of concomitant analgesic users (≥ 1 day per month) took them prophylactically (Table  3 ). It remains unclear whether overuse stems from lack of medical guidance or self-medication. Distinguishing physician-guided from self-directed use would improve intervention strategies. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are effective in about 80% of women with functional dysmenorrhea, but for persistent pain, prostaglandins have already formed, delaying relief. For severe symptoms, starting medication at or just before cramps and continuing every 6–8 h for 2–3 days is recommended [ 57 ]. Prolonged prophylactic use for headaches may worsen them and complicate withdrawal [ 29 ]. It is essential to verify whether prophylactic analgesics are medically supervised or self-administered. Counseling should support proper medication follow-up. The strength of this study lies in being the first detailed investigation of concomitant analgesic use and overuse among LEP users, identifying factors associated with loneliness and concomitant analgesic overuse through logistic regression analysis. However, several limitations exist. First, self-reporting and selection biases may affect results; physician-based diagnoses could allow more nuanced clinical discussions. Second, as an observational study, causality cannot be established, and reverse causality remains possible. Third, generalizability is limited since the study focused only on young women using LEP, excluding other contraceptive types. It is important to clarify what proportion use LEP for contraception versus symptom relief. Fourth, the absence of a non-LEP user comparison group restricts understanding of how loneliness and concomitant analgesic use relate among women with menstrual symptoms not treated hormonally.

This study provides a detailed examination of concomitant analgesic use and overuse among LEP users, a topic that has received limited prior attention. The observed association between loneliness and concomitant analgesic use highlights the potential influence of emotional and social factors on pain management behaviors. Notably, loneliness was not associated with analgesic overuse; rather, it was linked to concomitant use, which may in itself reflect a tendency toward higher overall medication consumption. This distinction implies that while loneliness may not directly drive excessive use, it could signal underlying patterns of frequent or habitual analgesic intake. Furthermore, the association between analgesic overuse and conditions such as endometriosis and low back pain underscores the importance of comprehensive monitoring strategies that integrate both physical and psychosocial dimensions, including self-tracking of menstrual symptoms. Addressing the broader psychosocial context—particularly loneliness—may foster more effective communication between patients and healthcare providers and support more personalized care. From both clinical and public health perspectives, analgesic overuse and loneliness should be recognized as modifiable factors, amenable to targeted intervention.

Defined as a distressing subjective feeling that arises from the discrepancy between one’s desired and perceived social relationships, loneliness is characterized by heightened emotional vulnerability, hypervigilance, and perseverative cognition [ 1 , 2 ]. It has been identified as a risk factor for cardiovascular disease, Parkinson’s disease, and Alzheimer’s disease [ 3 – 5 ], and has also been linked to suicidal ideation following the onset of the COVID-19 pandemic [ 6 ]. Previous research has demonstrated the strong association between loneliness and mental health issues such as depression and anxiety, particularly during the COVID-19 pandemic [ 7 ]. A recent network analysis among Chinese university students revealed that loneliness was centrally positioned within the symptom network and showed strong direct associations with both anxiety and depression symptoms. Specifically, feelings of isolation and lack of companionship were closely linked to nervousness, restlessness, and depressive mood, suggesting that loneliness may act as a key driver in the development or maintenance of internalizing symptoms in this population [ 8 ]. Furthermore, a longitudinal study using a nationally representative sample of older adults in the United States found that prior loneliness predicted regular, contemporaneous use of prescription medications for depression and anxiety [ 9 ]. Additionally, longitudinal findings suggest that loneliness is not only linked to psychological distress but also to physical pain, with inflammation potentially mediating this bidirectional relationship [ 10 ]. Loneliness tends to be higher among women, individuals without partners, and those living alone or without children [ 11 ]. Loneliness has been found to be significantly associated with disruptions in menstruation [ 12 ]. The female reproductive system is highly sensitive to both physical and psychological stress. While mild stress can motivate individuals to respond to changes and face challenges, high levels of stress may have detrimental effects on physical and psychological health. For example, activation of the corticotropin-releasing hormone system in response to stress can disrupt menstrual function [ 13 ]. Menstrual symptoms represent a major burden for women of reproductive age worldwide, adversely affecting their health status and quality of life. Various menstrual symptoms and related disorders have been studied extensively, including menorrhagia, premenstrual syndrome (PMS), primary dysmenorrhea, and premenstrual dysphoric disorder [ 14 – 23 ]. Among these, dysmenorrhea is one of the most common conditions impacting women’s quality of life and even their future pregnancies [ 24 ]. A survey of women aged 15 to 49 reported that 74% of menstruating women experienced painful symptoms related to menstruation [ 25 ]. Previous studies have classified the severity of dysmenorrhea, but few have examined whether analgesic use varies according to severity. Dysmenorrhea symptoms can be alleviated or improved by low-dose estrogen-progestin (LEP) therapy [ 26 ]. However, some women may still use additional analgesics, possibly because LEP alone is insufficient or due to poor adherence to treatment. In Japan, the prevalence of oral contraceptive (OC) use is reported to be only 2.9%, which is much lower than in countries such as France (33.3%) and others worldwide [ 27 ]. Moreover, the use of LEP mainly for contraception, rather than for treatment of menstrual pain, is not authorized in Japan. In addition, LEP medications are not available over-the-counter (OTC) in Japan and require a prescription. These restrictions may limit symptom control, necessitating concomitant use of analgesics. When loneliness and pain co-occur, it is plausible that analgesic use may continue primarily for pain relief. Analgesics are widely used globally as both prescription and OTC medications; however, overuse can lead to adverse effects such as gastrointestinal and renal dysfunction [ 28 ]. Frequent and prolonged use of analgesics may also result in more frequent headaches, impairing quality of life [ 29 ]. One notable consequence is medication overuse headache (MOH) [ 29 , 30 ]. The prevalence of MOH is reported to be 2.3% in Japan [ 31 ] and 1.8% in Sweden [ 32 ], with a higher incidence among women and middle-aged adults [ 31 ]. Patients suffering from headaches require education and counseling to reduce acute medication intake. The pathophysiology of MOH involves altered descending pain modulation, central sensitization, and biobehavioral factors [ 33 ]. However, the impact of women’s loneliness on medication use remains unclear. Therefore, a research gap exists due to the paucity of studies examining the interaction between menstrual symptoms, LEP use, psychosocial factors such as loneliness, and the risk of MOH. Understanding the relationship between loneliness and concomitant analgesic overuse among women using LEP may facilitate more effective medication management and follow-up. Poor sleep quality is frequently reported by young women with migraine and is often perceived as a trigger. Migraine and sleep disturbances may share underlying neurobiological mechanisms, including hypothalamic involvement, serotonergic and dopaminergic signaling, and dysfunction of the glymphatic system [ 34 ]. As poor sleep quality can increase pain sensitivity and potentially lead to greater analgesic use, its role should be considered when examining the complex relationship between loneliness and medication overuse [ 35 ]. Thus, the aim of this study was to investigate the prevalence and patterns of concomitant analgesic use and overuse among women using LEP, and to clarify the factors associated with loneliness and analgesic overuse. By examining these associations, this study seeks to contribute to a deeper understanding of how psychosocial stressors such as loneliness may influence self-medication behaviors in reproductive-aged women. The findings may inform clinical strategies for the management of menstrual pain and mental health, support more appropriate use of analgesics, and highlight the need for integrated care that addresses both physical and emotional wellbeing.

Supplementary Material 1 Supplementary Material 1